Exon Skipping Proves Effective in Mice with a Severe DMD-Like Disease

These latest exon skipping trial results are unique in that the mice were more severely affected by muscular dystrophy symptoms than mice in previous exon skipping trials. Team member Stephen Wilton at the University of Western Australia in Perth received MDA support on this study.

Mice with a severe disease closely resembling human Duchenne muscular dystrophy (DMD) have responded extremely well to a new "exon skipping" compound that targets the specific dystrophin gene error these mice have.

Researchers noted "a remarkable prevention of the dystrophic pathology and improvement of the muscle function" in these severely affected mice, which lack both the dystrophin and utrophin muscle proteins. (Mice in previous exon skipping trials lacked only dystrophin, the protein missing in DMD.)

This latest report adds to the evidence for exon-skipping-based drug development, which is already under way for DMD.

Kay Davies at the University of Oxford (United Kingdom) and colleagues published their findings online Oct. 20, 2009, in Molecular Therapy.

MDA supported Stephen Wilton at the University of Western Australia in Perth on this study. Wilton has been developing exon skipping in laboratory studies with MDA support for several years. MDA is supporting Davies for other research in DMD.

About DMD

DMD is a degenerative muscle disease caused by any of a number of mutations in the X-chromosome gene that carries instructions for the muscle protein dystrophin. Without dystrophin, muscle fibers are abnormally fragile and break down under the stress of contractions.

About exon skipping and DMD

The regions of genes that carry instructions for proteins such as dystrophin are known as "exons." During the processing of genetic information in cells, these exons are pieced together, while other information (in the form of "introns") is removed. Then, the final instructions are exported from the cell nucleus, at which time the cell can use them to make protein molecules.

Exon skipping compounds in development for DMD use molecules called "antisense" that block (keep cells from "making sense of") erroneous genetic instructions in particular exons. The goal is for the remaining, error-free exons to be spliced together to form the "recipe" for a functional dystrophin protein molecule.

About the new findings

The mice used in the new study were different from mice used in previous exon skipping studies in that they were missing both dystrophin and another muscle protein, utrophin, causing them to have severe symptoms that closely resemble the course of human DMD. (Unlike these research mice however, humans with DMD do not lack the utrophin protein.)

Mice that received six weeks of an exon skipping compound via injections into the abdomen produced nearly normal levels of apparently functional dystrophin protein in all the muscles the researchers examined, with the exception of the heart.

Along with the restoration of dystrophin protein, they experienced considerable improvement of their muscle function compared to untreated mice, and they lived much longer. These severely affected mice normally don't survive beyond 12 weeks, but at the close of the experiment, there were healthy-appearing, treated mice that were 26 weeks old.

Unfortunately, dystrophin production in the heart was minimal, differing from previously reported results. The researchers attribute this problem to the method used to deliver the treatment.

They say they delivered the treatment via intra-abdominal injections because these dystrophin-deficient/utrophin-deficient mice decline so rapidly and die so quickly that they have to be treated during the newborn period, when intravenous therapy is not feasible. They say intravenous delivery, a more likely route in humans, would be much more likely to reach the heart.